Neutrophils are important mediators in a variety of chronic inflammatory diseases affecting the airways, such as chronic obstructive pulmonary disease (COPD) and cystic fibrosis (CF). Neutrophil influx into these chronically inflamed airways propagates damage via multiple mechanisms, including oxidant injury and the release of proteolytic enzymes, leading to parenchymal lung injury and end-organ dysfunction.
The major chemoattractants for neutrophils in these conditions are glutamic acid-leucine-arginine-positive (ELR+) CXC chemokines including IL-8, growth-related oncogene (GRO)-α, GRO-β, and GRO-γ in humans and KC and MIP-2 in mice. Nonspecific collagen-derived fragments have also been reported to induce neutrophil chemotaxis in murine models. Elastin fragments ending with proline-glycine have been shown as having the capacity to cause fibroblast and monocyte chemotaxis and, to a lesser degree, neutrophil chemotaxis.
Recent models of airway inflammation indicate that protease/antiprotease imbalance is a prime feature in several pulmonary diseases including COPD and CF. One class of proteases recently felt to play an important role in airway remodeling in lung disease are matrix metalloproteases (MMPs), a family of zinc containing endopeptidases with the capacity to degrade multiple components of the extracellular matrix. Recently, the presence and enhanced activity of discrete MMPs has been observed in the sputum of patients with CF, including MMP-8 and MMP-9 (Gaggar et al., Am. J. Physiol 293:L96-L104 (2007)). Despite recent evidence that implicates MMP-9 as involved in the generation of PGP, MMP-9 does not demonstrate the substrate specificity to liberate PGP directly from collagen by itself. Thus, one or more other proteases are likely involved. As such, the specific proteolytic mechanism for the release of this peptide from collagen is unknown.